The present invention relates to novel cycloalkyl-diamines, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of Human African Trypanosomiasis (HAT), Chagas Disease, Leishmaniasis, Malaria and similar parasitic diseases in humans and animals.
Human African Trypanosomiasis (HAT) is a disease spread by trypanosoma brucei, a parasitic organism which is transmitted to humans primarily via bites from the tsetse fly. HAT is often referred to as “sleeping sickness” because of the symptoms that emerge in patients who have progressed to the advanced, or Stage 2, level of infection following exposure to the CNS by the parasite; this latter stage of the disease is typically fatal (Jacobs and Ding, Annual Reports in Medicinal Chemistry, (2010), 45:277-294; Rollo, in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 12th Ed., (2011), 1419-1441).
The disease is found in two forms, depending on the causative parasite (Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense). T. b. gambiense is primarily found in central and western Africa and causes a chronic condition that can remain in a passive phase for months or years before symptoms emerge. T. b. rhodesiense is found in southern and eastern Africa; symptoms of infection generally emerge in a few weeks and are more virulent and faster developing than T. b. gambiense. Approximately one-half million inhabitants of sub-Saharan Africa are potentially infected each year by the hemolymphatic, Stage 1, form of HAT. Symptoms include fever, headaches, joint pain and itching, as well as severe swelling of lymph nodes; chronically HAT symptoms include anemia, endocrine, cardiac and kidney dysfunctions.
Nearly 10,000 deaths have been reported as recently as 2010 from neurological, or Stage 2, HAT (Simarro, International Journal of Health Geographics, (2010), 9:57). Symptoms for these patients are generally more severe, including confusion, reduced coordination and disruption of the sleep cycle, as well as progressive mental deterioration leading to coma and death. Damage as a result of Stage 2 HAT is irreversible.
During the past decade there has been a renewed interest in developing safer, more efficacious HAT drugs, with an increased recognition of the impact of this disease upon quality of life for patients and their society in general. In fact, little had been accomplished over the past three decades to identify and develop safer and more efficacious medications for HAT, particularly for patients suffering from the advanced stage of this disease. The drugs most commonly used are essentially antifungal compounds, acting directly on the invasive protozoa in the bloodstream; poor penetration of the blood-brain barrier (BBB) has limited the use of some of these drugs to treatment of the hemolymphatic first stage of HAT. The most commonly prescribed treatments include pentamidine, suramin, melarsoprol, eflornithine and the combination therapy NECT (nifurtimox plus eflornithine). However, a growing concern in recent years is the issue of cross-resistance to some of the currently available medications. This is especially the case with pentamidine and arsenicals like melarsoprol (see Koning, Trends in Parasitology, (2008), 24(8):345-349).
The organism responsible for HAT, Trypansoma brucei (T. brucei), is also related to other parasitic species which can cause severely debilitating symptoms in humans and animals. Chagas disease, for example, caused by the related parasite Trypanosoma cruzi, is prevalent in a number of South American countries, affecting as many as 10 million individuals. It has also been detected in cattle, causing financial hardship for ranches as well as individual herders. Fatalities from Chagas disease are estimated to be about 21,000 per year and usually involve cardiovascular damage leading to death for the most seriously infected patients. Leishmaniases, detected in several forms, are estimated to affect as many as two million people on four continents while malaria, spread by exposure to one or more Plasmodium organisms, continues to afflict humans throughout the world.
One of the most commonly used HAT treatments for Stage 1 exposure is pentamidine. This diamidine compound has been extensively studied with respect to structure-activity relative to the replacement of the 1,5-dioxopentyl portion of the molecule by a variety of aryl and heteroaryl rings (e.g., Tidwell (2006) Journal of Medicinal Chemistry, 49:5324). However, little has been done to enhance pentamidine's brain concentration, e.g., through the incorporation of functional groups associated with enhanced CNS-penetration, such as those found in the most effective antipsychotic and antidepressant drugs currently on the market. Thus, it is possible that new treatments which target the T. brucei parasite and HAT could demonstrate sufficient efficacy against these related parasitic organisms and would thus be of immense value as antiparasitic therapeutic agents (Silva (2007) Biochemical Pharmacology 73:1939-1946).